1. Field of Invention
This invention relates to agonist peptides of basic fibroblast growth factor (bFGF) and the method of reduction of wrinkles on skin, darkening of hair and acceleration of wound healing.
2. Description of Related Art
Basic fibroblast growth factor (bFGF) also known as FGF2, so named because it contains a high number of basic amino acid residues (Lysin, Arginie and Histidine) is a potent mitogen for a variety of cell types including melanocytes, keratinocytes, and the major cell type in the epidermal unit and fibroblasts located in the dermis of skin. Both bovine and human bFGF were isolated and the genes expressing this product were sequenced and cloned. In addition, bFGF was found to be expressed in a wide variety of tissue types including placenta, keratinocytes, and fibroblasts.
We have earlier described that bFGF may be involved in repigmentation of vitiligo macules, a pigmentary disorder characterized by patchy depigmentation of skin (Ramaiah, A; Puri, N; and Majamdar, M. A new hypothesis for etiology of vitiligo in Acte Derma Venereol (Stockholm), 1989, 69:323-327). This idea was tested first on the in-vitro melanocyte cell cultures from the uninvolved areas of untreated vitiligo subjects and later on mixed cell cultures of melanocytes and keratinocytes obtained from the uninvolved areas of untreated vitiligo subjects. The results demonstrated that bFGF corrects all the abnormalities of melanocytes obtained from the uninvolved areas of untreated vitiligo subjects. An animal model was developed to resemble vitiligo to test the efficacy of interdermal injection bFGF on the rate of repigmentation of depigmented ear lobes of Guinea pigs and depigmented ear lobes of Guinea pigs and depigmented skin patches of Yucatan swine. They were found effective. Peptides ranging from deca peptide to 24 amino acid long peptide were tested for the efficacy to repigment the depigmented ear lobes of Guinea pigs and the depigmented skin patches of Yucatan swine. These peptides were shown to be specific since other growth factors like epidermal growth factor or peptide 1-12 of bFGF did not have any effect on the repigmenting of depigmented patches on the experimental animals.
Patents of interest describing bFGF or peptides described above and the formulation for their penetration through intact skin include U.S. Pat. No. 6,143,723; AU Patent No. 722626; Indian Patent Nos. 185613, 186437, and 185703.
The peptides were tested on human volunteers suffering from vitiligo in the various phases of clinical trials in India and found to be successful in repigmenting about more than 80% of the volunteers with stable generalized vitiligo and segmental vitiligo.
Skin is subject to aging and is visible to the naked eye. The aging process of skin can be divided into chrono aging and photo aging. The former is a normal aging process and can be accelerated by the exposure of skin to sun, which is known as photo aging. In addition, skin is subject to deterioration through dermatological disorders, and environmental abuse.
Exposure of white, very fair skin to ultraviolet radiation results in more wrinkling of skin than the more pigmented skin. Skin wrinkles are a reminder to the individual that he/she is looking older and, therefore, individuals like to reduce skin wrinkles by application to the skin of various cosmetic creams and/or moisturizers. Failing that, the use of various forms of cosmetic surgery which treat or delay the visible signs of chrono aging/photo aging such as wrinkles, lines, sagging etc. can be attempted.
There is a vast amount of epidemiological literature relating to thinning of skin to aging. Collagen-1 represents more than 70% of the dermis of the skin. (Uitto J. Connective tissue biochemistry of the aging dermis: Age related alterations in collagen and elastin: Dermatio. Clin (1986) 4:433-46). Dermal collagen content peaks in the third decade of life and declines gradually at a rate approximately 1% per year thereafter in men and women (Artho P. Skin thickness and collagen content in some endocrine, connective tissue and skin diseases. Acta derm. Veneroeol Suppl (Stockh) 1972: 69:1-48. Meema H E, Sheppard R H, Roentgen graphic visualization and measurement of skin thickness and its diagnostic application to acromegaly, Radiology (1964); 82:411-7, Shuster S, Black M M, Mc Vitie E:. The influence of age and sex on skin thickness, skin collagen and density Br J Dermatol (1975); 93:639-43, Shuster S Bottoms E senile feneration of skin collagen in men. In women it may be so after the fifth decade of life.
Collagen is the predominant matrix skin protein and is known to impart tensile strength to skin. Decorin is proteoglycan, which is known to be important for controlled and correct deposition of collagen in the extracellular matrix of skin. It is also known in the art that the levels of collagen and decorin in skin are significantly reduced with age and/or photo damaged skin. Many studies had shown that the levels of collagen type 1 in skin are decreased with age and/or with increased photo damage (Lavaker R, Jour. Invest. Dermatol (1979); 73:59-66 Griffiths et al New. Eng J. med (1993); 329, 5300535). In the case of decorin, it has been shown that mRNA expression of the proteoglycan is greatly reduced in photo-damaged skin in vitro (Bernstein et al. Lab Invest (1995); 72:662-669). The reduction of the levels of these skin proteins is accordingly associated with collagen, elastin also is lost with age. So the skin gets thinner with age and has a tougher time getting enough moisture to the epidermis. At about the same time the fat in the subcutaneous layer (which gives skin a plump firm appearance) also begins to disappear. The epidermis begins to sag, and wrinkles form. Wrinkles are then prone in the face where facial muscle contractions have been repeated over many years.
In addition to gradually aging and sun exposure there are a number of other factors that can contribute increased wrinkles. Some of these can be controlled, while others cannot. The most common factors that determine wrinkle occurrence include the following:
Heredity
Skin type
Smoking
Hair style
Sun exposure
Drug use
Wrinkles on the face are due to repeated nerve stimulation that results in repeated facial muscle contractions, in addition to reduction in the amount of collagen, elastin and subcutaneous fat in the skin. All anti-wrinkling agents which reduce the nerve stimulation and, thus, facial muscle contractions, can help in the reduction of fine lines and wrinkles on the face.
Wrinkle reduction on the rest of the skin on the body, including the skin on the face, should essentially be by increasing the synthesis of collagen retention in the skin of moisture.
It is well known in the art that retinoic acid is a potent anti-aging agent and induces dermal repair of photo damaged skin. It was shown that wrinkle effacement and dermal repair following topical treatment of skin with retinoic acid arises through new collagen deposition and synthesis in skin (Griffiths et al New, Eng. J, Med (1993); 329, 530-535).